More than 200 million people worldwide are estimated to be chronically infected with HCV and as a result, at risk for developing life-threatening liver diseases. The only treatment currently available is a combination therapy of pegylated interferon and Ribavirin, a nucleoside analogue. Unfortunately this combination has exhibited limited efficacy in less than half of treated patients, as well as being plagued with treatment- limiting side effects and toxicity. In addition, increasing reports of drug resistance to investigational small molecules in clinical trials are emerging, underscoring the need for new and more effective treatments. A number of modified nucleosides have exhibited potent activity as inhibitors of HCV polymerase, however problems with ineffective delivery, toxicity, instability and/or poor pharmacokinetics have rendered many promising analogues unsuitable, thus many researchers are turning to use of a prodrug, or masking group, on the 5'-OH of the nucleoside, to overcome these problems. This application focuses on a series of expanded purine nucleoside analogues that we anticipate will exhibit potent activity against the HCV RNA-dependent RNA polymerase (RdRp) NS5B due to a number of strategically designed structural features. The impact of this application is two-fold; one, the medicinal discoveries could ultimately have a global impact, as more effective HCV treatments are desperately needed. In addition, the basic scientific impacts include expanding the breadth of our knowledge of drug delivery methods for specific targeting of the HCV NS5B polymerase, as well as liver cells. In addition, new and improved methodology for nucleoside analogue synthesis will be investigated. As such, the scientific impact of this work goes beyond just global health research, but will also provide valuable training for students, as the synthetic organic and drug delivery methodologies and the information obtained about polymerases will be highly applicable across a broad scope of diseases. PUBLIC HEALTH RELEVANCE: More than 200 million people worldwide are estimated to be chronically infected with the hepatitis C virus (HCV) and the only currently available treatment is efficacious in less than half of treated patients, as well as being plagued with treatment-limiting side effects and toxicity. This application focuses on a series of nucleoside analogues that should exhibit potent and synergistic activity against the HCV RNA-dependent RNA polymerase (NS5B due to a number of strategically designed structural features. The impact of this project goes beyond just global health research, but will also provide valuable hands on training for students. Moreover, the information obtained about nucleoside prodrugs and HCV polymerases will be highly applicable across a broad scope of viral diseases.